Granulocyte colony-stimulating factor has no adverse effects on atherosclerotic lesions in high cholesterol-fed miniature Swine.
ABSTRACT Granulocyte colony-stimulating factor (G-CSF) is widely used to mobilize peripheral blood stem cells, and expected to restore cardiac function for patients with coronary artery diseases as a consequence of progression of atherosclerosis. Safety issues related to the administration of G-CSF to these patients, however, are still under study. The animal model for atherosclerosis was produced by feeding miniature swine a high-cholesterol diet for 3 months. G-CSF (5 or 10 microg/kg/day) was given to the animal model by daily subcutaneous injections for 10 days and 20 main arteries were evaluated pathologically. In addition, the general toxicological effects were studied on clinical signs, body weight, hematology, blood chemistry and pathology. In the G-CSF-treated groups, a variety of changes related to the major pharmacological activity of G-CSF including an increase in white blood cell (WBC) counts were observed. In many arteries, atherosclerotic lesions similar to Type I-V of the proposed classification by the American Heart Association were observed. No effects of the G-CSF treatment were seen on the histopathological findings, incidence, severity or distribution of atherosclerotic lesions. In addition, no infiltration of neutrophils to the lesions was observed. These findings suggest that the administration of G-CSF causes neither exacerbation or modification of atherosclerotic lesions nor adverse changes despite that a sufficient increase in WBC counts could be achieved in the peripheral blood.
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ABSTRACT: Bone-marrow stem-cell transplantation has been shown to improve cardiac function in patients with myocardial infarction. We examined the feasibility and efficacy of granulocyte-colony stimulating factor (G-CSF) therapy and subsequent intracoronary infusion of collected peripheral blood stem-cells (PBSCs) in such patients. We prospectively randomised 27 patients with myocardial infarction who underwent coronary stenting for the culprit lesion of infarction into three groups; cell infusion (n=10), G-CSF alone (n=10), and control group (n=7). Changes in left ventricular systolic function and perfusion were assessed after 6 months. By December, 2003, seven patients from the cell infusion group, three from the G-CSF group, and one from the control group had been assessed. G-CSF injection and intracoronary infusion of the mobilised PBSC did not aggravate inflammation and ischaemia during the periprocedural period. Exercise capacity (mean treadmill exercise time: 450 s [SD 178] at baseline vs 578 s  at 6 months' follow-up, p=0.004), myocardial perfusion (perfusion defect 11.6% [9.6] vs 5.3% [5.0], p=0.020) and systolic function (left ventricular ejection fraction 48.7% [8.3] vs 55.1% [7.4], p=0.005) improved significantly in patients who received cell infusion. However, we noted an unexpectedly high rate of in-stent restenosis at culprit lesion in patients who received G-CSF, and therefore we stopped enrollment. G-CSF therapy with intracoronary infusion of PBSC showed improved cardiac function, and promoted angiogenesis in patients with myocardial infarction. However, aggravation of restenosis could be a serious problem. In future studies with G-CSF based stem-cell therapy, patients should be carefully monitored for unexpected effects.The Lancet 04/2004; 363(9411):751-6. · 39.06 Impact Factor
- Blood 06/2002; 99(9):3089-101. · 9.06 Impact Factor
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ABSTRACT: Myocardial infarction leads to loss of tissue and impairment of cardiac performance. The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time. Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation; these events promote structural and functional repair. This high degree of stem cell plasticity prompted us to test whether dead myocardium could be restored by transplanting bone marrow cells in infarcted mice. We sorted lineage-negative (Lin-) bone marrow cells from transgenic mice expressing enhanced green fluorescent protein by fluorescence-activated cell sorting on the basis of c-kit expression. Shortly after coronary ligation, Lin- c-kitPOS cells were injected in the contracting wall bordering the infarct. Here we report that newly formed myocardium occupied 68% of the infarcted portion of the ventricle 9 days after transplanting the bone marrow cells. The developing tissue comprised proliferating myocytes and vascular structures. Our studies indicate that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease.Nature 05/2001; 410(6829):701-5. · 38.60 Impact Factor